Continuous-infusion 5-fluorouracil in metastatic colorectal cancer patients pretreated with bolus 5-fluorouracil: clinical evidence of incomplete cross-resistance.
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Colorectal Neoplasms↗
Biomedical subjects
A Falcone
Publications and source records attributed to A Falcone.
Oral doxifluridine in elderly patients with metastatic colorectal cancer: a multicenter phase II study.
BACKGROUND: Cancer chemotherapy in elderly patients is an important and under-researched area. Doxifluridine is a fluoropyrimidine derivative and is activated to 5-fluorouracil by uridine phosphorylase, which is more highly expressed in malignant cells. Because of the high bioavailability and low toxicity of oral doxifluridine we conducted this phase II trial to evaluate the feasibility, toxicity and activity of a home therapy with oral doxifluridine in elderly metastatic colorectal cancer patients. PATIENTS AND METHODS: Forty-three elderly metastatic colorectal cancer patients entered the study: their median ECOG performance status was 1 (0-2) and median age 74 years (69-83), the predominant site of metastasis was liver and all but one of the patients had received no previous chemotherapy. Doxifluridine was given orally at the initial daily total dose of 2250 mg for 4 consecutive days every week. The daily dose was reduced to 1500 mg if toxicities greater than grade 2 (WHO) occurred. RESULTS: Forty-two patients are evaluable for toxicity: treatment was well tolerated, with the most common side effect being diarrhea, severe in 7 (17%) patients (6 grade 3 and 1 grade 4). Thirty-six patients are evaluable for response and 2 complete and 3 partial responses have been observed (response rate 14%; 95% confidence limit interval 5%-29%). CONCLUSIONS: This study demonstrates that a home therapy with oral doxifluridine in elderly advanced colorectal cancer patients is feasible, with a relatively low rate of toxicity, and has moderate activity, comparable to that of intravenous 5-fluorouracil. Therefore, this treatment may be considered for the management of advanced colorectal cancer in the elderly.
Administration, Oral↗
Double 5-fluorouracil modulation with folinic acid and recombinant alpha-2B-interferon. A phase I-II study in metastatic colorectal cancer patients.
Twenty-two patients with metastatic colorectal cancer entered a Phase I-II trial to assess the maximum tolerable dose of alpha-2B-interferon administered intramuscularly three times per week in combination with fixed doses of 5-fluorouracil (450 mg/m2 IV for 5 days, and, from day 28, weekly) and folinic acid (200 mg/m2 IV before 5-fluorouracil) and the efficacy of this combination. Diarrhea and mucositis were the most frequent 5-fluorouracil-related toxicities and were > or = ECOG grade 3 in 23% and 18% of patients, respectively. Of 15 patients receiving interferon > or = 9 x 10(6) IU, 10 required interferon dose reduction mostly because of severe fatigue, anorexia, and declining performance status. Among 19 patients evaluable for response, 3 achieved a partial response and 1 a complete response for an overall response rate of 21% (95% confidence interval, 6-46%). In conclusion, our study demonstrates that IFN-alpha 2B at doses higher than 6 x 10(6) IU intramuscularly three times per week in the combination with 5-fluorouracil and folinic acid we used is too toxic for the majority of patients; this combination has moderate activity in metastatic colorectal cancer, although similar response rates have been reported, with less toxicity, with 5-fluorouracil plus folinic acid without IFN-alpha. A larger Phase III study would be required to determine the value of IFN-alpha in this combination.
Aged↗
Protective effects of pidotimod against experimental bacterial infections in mice.
Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) protected mice against experimental bacterial infections in different experimental models. In all tests the drug's effect was measured as protection from death. The activity of pidotimod was evident and statistically significant after 5 administrations before the bacterial challenges. Pidotimod was active against many bacterial species infections, its active dosages ranging from 0.01 to 100 mg/kg i.p. x 5 times. Pidotimod showed against some bacterial infections a protection similar or better than those of bestatin, N-acetylmuramyl-L-Ala-D-isoGlu-OH and tuftsin. It showed high protection against bacterial infections in cyclophosphamide-immunodepressed mice. Finally, pidotimod showed an additive or synergic activity in combination with beta-lactam antibiotics (cefotaxime, ampicillin) against bacterial infections in mice.
Adjuvants, Immunologic↗
General pharmacology of pidotimod and testing for drug interactions.
Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) is a new biological response modifier. General pharmacology and interactions with some drugs were tested. The drug, at doses of 200 mg/kg i.p. and 400 mg/kg p.o., did not affect the normal behaviour, did not modify the responses to stimulation of autonomic nervous system or central nervous system. Pidotimod did not display any cardiovascular or respiratory effect up to 125 mg/kg i.v. in 3 animal species. The drug did not show antimicrobial or antifungal activities nor interact with some of the most common therapeutics (antibiotics, tolbutamide, pentobarbital, antihypertensives, chlorothiazide, warfarin, non-steroidal antiinflammatory agents). On the basis of these results pidotimod shows a safe profile; moreover it does not interact with many therapeutic agents.
Animals↗
A phase I-II study of oral doxifluridine plus radiotherapy in radiosensitive tumors of the pelvic region.
AIMS AND BACKGROUND: Fluoropyrimidines have shown synergic effects in combination with radiotherapy in several tumor types. Doxifluridine is a novel 5-fluorouracil (5-FU) prodrug which is transformed into 5-FU in neoplastic tissue. This would imply enhancement of radiotherapy by 5-FU in neoplastic tissue, where the drug is concentrated higher than in surrounding healthy tissues. METHODS: A phase I-II study was carried out on 10 patients with radiosensitive tumors of the pelvic area (4 uterine carcinomas). Escalating doses of oral doxifluridine were administered in combination with standard radiotherapy to assess the efficacy and toxicity profile of the combined treatment. The 9 evaluable patients (3 groups of 3 patients each) received oral doxifluridine, at daily doses of 500, 750, or 1000 mg, for 6 consecutive weeks in combination with a standard (1.8-2.0 Gy) dose of radiotherapy. Assessment of physical and laboratory parameters was made at baseline, then weekly up to the end of the treatment and at follow-up. RESULTS: At the final evaluation, one patient with a diagnosis of uterine carcinoma showed a complete response that lasted 10 weeks. One patient had a partial response, and 7 patients had no change. The most frequent adverse events were gastrointestinal: 27 episodes of mild to moderate nausea/vomiting and diarrhea. Three patients complained of severe diarrhea of 5-7 days duration: all patients spontaneously recovered. There were no significant changes in laboratory or clinical parameters, and no serious toxicity requiring reduction or interruption of the radiotherapy. CONCLUSIONS: The maximum tolerated dose of oral doxifluridine in combination with standard radiotherpay was assessed at 1000 mg/patient/day (equivalent to 36-38 g monthly, previously reported as mTD in phase I studies).
Administration, Oral↗
Alpha-2B-interferon plus floxuridine in metastatic renal cell carcinoma. A phase I-II study.
BACKGROUND: Both alpha-interferon and floxuridine are active in metastatic renal cell carcinoma (MRCC); the two agents have demonstrated antitumor synergism and different clinical toxicities. The purpose of this study was to determine the maximum tolerable dose (MTD) of floxuridine (FUDR), administered as a constant continuous infusion for 14 days every 28 days, in combination with fixed doses of alpha-2B-interferon and to preliminarily evaluate the antitumor activity of this combination. METHODS: Sixteen patients entered the study; six had previously received alpha-interferon. Alpha-2B-interferon was administered at the dose of 10 x 10(6) IU intramuscularly 3 times/week and floxuridine at the starting daily dose of 0.075 mg/kg. This dose was escalated at each subsequent cycle up to dose-limiting toxicity. RESULTS: Most common toxicities included fever and flue-like symptoms, fatigue, anorexia, diarrhea, mucositis, and nausea, and 55% of patients experienced greater than or equal to Grade 2 toxicity, mostly diarrhea, for floxuridine doses greater than 0.125 mg/kg/d. Among 15 evaluable patients, 1 achieved a complete response and 4 achieved a partial one (33%; 95% confidence interval, 12-62%). Three partial responses were obtained in patients pretreated with alpha-interferon plus vinblastine. CONCLUSIONS: The combination of alpha-2B-interferon and floxuridine is feasible, and in our regimen the recommended daily dose of floxuridine for Phase II studies was 0.125 mg/kg. This combination is active in metastatic renal carcinoma, but further studies are needed to determine whether alpha-2B-interferon has added anything to the FUDR infusion or vice versa.
Adult↗
Myelomatous nodular lesions of the liver: diagnosis by ultrasound-guided fine-needle biopsy.
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Biopsy, Needle↗
The effect of scrubbing and irrigation with normal saline, povidone iodine, and cefazolin on wound bacterial counts in a guinea pig model.
This study examines the effects of povidone iodine, normal saline, and cefazolin alone and after scrubbing on bacterial counts in contaminated animal lacerations. Twelve albino guinea pigs each received four lacerations inoculated with a standard inoculum of Staphylococcus aureus. Twelve hours after inoculation, each wound was biopsied to ensure contamination and then either treated or left as an untreated control. One wound on each animal was an untreated control. The remaining three lacerations on six pigs were irrigated with cefazolin (CZ) solution, normal saline, or 1% (wt/vol) povidone iodine solution (PI). Three lacerations on another six pigs were treated with 20% poloxamer 188 scrub (scrub) alone, scrub followed by PI irrigation (SCR/PI), or scrub followed by CZ irrigation (SCR/CZ). Quantitative bacteriology was performed on tissue biopsies 2 hours (time 1), 7 hours (time 2), and 12 hours (time 3) after irrigation. Posttreatment counts for PI, CZ, and normal saline irrigation were not different from control or one another (P > .05). Bacterial counts for SCR/PI were significantly lower than control (P < .05) for all posttreatment biopsies (1.8 to 2.9 mean log(10) decrease). SCR/CZ was significantly lower than control (P < .05) at times 2 and 3 only (1.7 to 2.0 mean log(10) decrease). In this guinea pig model, cleansing 12-hour-old lacerations contaminated with S aureus using SCR/PI or SCR/CZ significantly reduced bacterial counts over 12 hours.
Animals↗
Nodular lesions of the liver in multiple myeloma: a role for cytoadhesion molecules?
Two patients with multiple myeloma and in vivo macroscopic nodular lesions of the liver are presented. The clinical aspects of this very unusual condition are briefly reviewed. In particular, the expression on neoplastic plasma cells of the cytoadhesion molecules CD56 and CD11a, which are involved in the cellular process of recirculation and homing, suggests a possible role for such markers in this atypical localization of the disease.
Aged↗
Activity of the new immunostimulant PGT/1A against experimental bacterial infections.
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Adjuvants, Immunologic↗
ACTH fragments reverse experimental haemorrhagic shock in rats.
Hypovolemic shock was produced in rats by withdrawing about 50% of estimated total blood volume. Following mean arterial pressure stabilization in the range of 25-27 mmHg, the rats were given intravenous ACTH (1-4) (4-9) (4-10) (5-10) (1-10) in comparison with ACTH (1-24). The ACTH fragments, administered within 5 min after shock induction, promptly and dose-dependently improved mean arterial pressure and survival of rats; the ACTH (1-10) showed an activity similar to that of ACTH (1-24) whereas the other fragments were less active.
Adrenocorticotropic Hormone↗
Treatment of plasma cell leukaemia and resistant/relapsed multiple myeloma with vincristine, mitoxantrone and dexamethasone (VMD protocol)
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Aged↗
Benzylacyclouridine reverses azidothymidine-induced marrow suppression without impairment of anti-human immunodeficiency virus activity.
Increased extracellular concentrations of uridine (Urd) have been reported to reduce, in vitro, azidothymidine (AZT)-induced inhibition of human granulocyte-macrophage progenitor cells without impairment of its antihuman immunodeficiency virus (HIV) activity. Because of the clinical toxicities associated with chronic Urd administration, the ability of benzylacyclouridine (BAU) to effect, in vivo, AZT-induced anemia and leukopenia was assessed. This agent inhibits Urd catabolism and, in vivo, increases the plasma concentration of Urd in a dose-dependent manner, without Urd-related toxicity. In mice rendered anemic and leukopenic by the administration of AZT for 28 days in drinking water (1.5 mg/mL), the continued administration of AZT plus daily BAU (300 mg/kg, orally) partially reversed AZT-induced anemia and leukopenia (P less than .05), increased peripheral reticulocytes (to 4.9%, P less than .01), increased cellularity in the marrow, and improved megaloblastosis. When coadministered with AZT from the onset of drug administration, BAU reduced AZT-induced marrow toxicity. In vitro, at a concentration of 100 mumol/L, BAU possesses minimal anti-HIV activity and has no effect on the ability of AZT to reverse the HIV-induced cytopathic effect in MT4 cells. The clinical and biochemical implications of these findings are discussed.
Anemia↗
Different effect of benzylacyclouridine on the toxic and therapeutic effects of azidothymidine in mice.
It has been reported that in vitro uridine (Urd) can reverse azidothymidine (AZT) cytotoxicity without decreasing anti-human immunodeficiency virus (HIV) activity. Our studies in mice have shown that daily oral doses of benzylacyclouridine (BAU), an inhibitor of Urd breakdown, also reduces AZT hematologic toxicity, presumably by elevating the plasma concentration of Urd. We now extend these murine studies and report the effect of various doses of exogenous Urd, various doses of BAU, or the combination of BAU and Urd, administered daily, on AZT-induced toxicity. In mice receiving concomitant AZT, daily doses of Urd of 1,000 to 2,000 mg/kg increase peripheral reticulocytes and slightly reduce AZT-induced hematologic toxicity. However, the range of effective doses is narrow, and higher doses of Urd (greater than 3,000 mg/kg/d) significantly enhance hematologic toxicity. At its most effective dose, (2,000 mg/kg/d), Urd produces 28% mortality. In contrast, BAU doses up to 300 mg/kg/d reduced AZT-related hematologic toxicity in a dose-dependent manner without mortality. Higher daily doses of BAU and the combination of BAU with low doses of Urd were not more effective. Studies conducted in mice infected with the Rauscher murine leukemia virus (RLV) indicate that BAU does not impair the antiretroviral effect of AZT when administered at doses that reduce AZT-induced anemia and leukopenia. These findings may be significant for the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex.
Acquired Immunodeficiency Syndrome↗
5-Fluorouracil enhances azidothymidine cytotoxicity: in vitro, in vivo, and biochemical studies.
Preliminary in vitro studies suggest that the combination of 5-fluorouracil (FUra) and 3'-azido-3'-deoxythymidine (AZT) is more cytotoxic than either agent alone. Therefore, a biochemical and therapeutic evaluation of this combination was initiated. Quantitation of the cytotoxicity of FUra plus AZT against the growth of HCT-8 cells in vitro revealed that 1 microM FUra (approximately 10% inhibitory concentration) increased the cytotoxicity of AZT and decreased its 50% inhibitory concentration by 60%. Similarly, incubating HCT-8 cells in 5 microM AZT (approximately 10% inhibitory concentration) decreased the 50% inhibitory concentration of FUra by over 50%. Biochemical analysis indicated that AZT did not affect FUra-induced inhibition of thymidylate synthase or [3H]-FUra incorporation into nucleic acids. In contrast, incubation in 5 microM FUra increased the incorporation of [3H]-AZT (5 microM) into the nucleic acid fraction of these cells by 52% (P less than 0.05). Therapeutic evaluation of this combination in athymic (nude) mice bearing HCT-8 xenographs revealed that, while weekly FUra (85 mg/kg) or AZT (600 mg/kg) exerts minimal antineoplastic activity (after 4 courses, treatment/control = 0.81 and 0.70, respectively), their combination, at the same doses, inhibited tumor growth by nearly 70% (P less than 0.01 versus FUra alone). FUra-related host toxicity was not increased by the addition of AZT. Higher doses of FUra alone were not more effective than FUra plus AZT. In vivo, AZT did not affect the incorporation of [3H]-FUra into the nucleic acid fraction of various murine tissues, including HCT-8 xenografts. FUra, however, increased [3H]-AZT incorporation into nucleic acids in a tissue-specific manner. In the presence of FUra, the incorporation of [3H]-AZT in spleen, liver, and gut increased 40, 21, and 4%, respectively, while in HCT-8 xenografts [3H]-AZT incorporation increased more than 2-fold. Analysis of the activities of selected enzymes involved in pyrimidine metabolism suggests that this tissue-specific effect may be related to the pyrimidine salvage capacity of these tissues. These findings are described in light of their potential impact on human colon cancer chemotherapy.
Animals↗
The thyrotropin releasing hormone analogue, RGH 2202, reverses experimental haemorrhagic shock in rats.
Hypovolemic shock was produced in rats by withdrawing about 50% of the estimated total blood volume. Following mean arterial pressure stabilization in the range of 22-23 mm Hg, the rats were given an i.v. bolus injection of L-6-ketopiperidine-2-carbonyl-L-leucyl-L-proline amide (RGH-2202) to be compared with thyrotropin-releasing hormone (TRH). RGH-2202, administered within 5 min following shock induction, dose dependently improved the mean arterial pressure and survival of the rats. The activity of RGH-2202 was superior to that of TRH after i.v. administration; both drugs showed a lower activity after i.m. administration.
Animals↗
Recombinant alpha-2a interferon plus vinblastine in the treatment of metastatic renal cell carcinoma.
Twenty consecutive metastatic renal cell carcinoma patients were treated with a combination of recombinant alpha-2a interferon (18 X 10(6) U three times weekly) and vinblastine (0.1 mg/kg every 3 weeks). Two patients (10% response rate; 95% confidence limits 1.23-31.7%) achieved partial response and 11 (55%) stable disease. Toxicity was significant but always acceptable: most frequently, patients complained of fever and flu-like symptoms (18 of 19 patients), fatigue (18 of 19 patients), worsening in performance status (15 of 19 patients), and anorexia (15 of 19). The combination of recombinant alpha-2a interferon and vinblastine is active in renal cell carcinoma.
Adult↗